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GERERAL ANESTHESIA AND PHARMACOLOGY OF GENERAL ANESTHETICS Amir B. Channa FFARCS,DA(ENG) Department of Anesthesia & Intensive Care King Khalid University Hospital Riyadh Slide 2 Slide 3 Anesthesia Types Local Anesthesia: loss of sensory perception over a small area of the body Regional Anesthesia: loss of sensation over a specific region of the body (e.g. lower trunk) General Anesthesia: loss of sensory perception of the entire body Slide 4 Anesthesia The administration of drugs that alleviate pain or other sensation and movement Local Effects a specific region of the PNS General Effects CNS General anesthesia is a state of reversible loss of consciousness for the purpose of carrying out surgery. Slide 5 Desirable components of anesthesia 1.Immobility in response to noxious stimulus 2.Anxiolysis 3.Amnesia 3. Analgesia 4. Unconsiousness 5. Muscle relaxation 6. Loss of autonomic reflexes Slide 6 Historical Perspectives History First attempts Egyptian - compression Grecian - wine and mandragora Scythian - hemp Indian - hemp Chinese - hemp Slide 7 Effects of general anesthesia Low Dose Effects Amnesia Euphoria Analgesia Hypnosis Excitation Hyperreflexia High Dose Effects Deep sedation Muscle relaxation Diminished motor responses Diminished autonomic responses Myocardial protection from ischemia Cardiovascular/respiratory depression Hypothermia Nausea, vomiting Death (1 per 250,000) Slide 8 Before Anesthesia Surgery uncommon Aseptic technique unknown Surgical pain relief alcohol, hashih, opium physical methods (ice, ischemia) unconsiousness (blow to head, strangulation) simple restraint most common Slide 9 Slide 10 Slide 11 GasVolatile liquids*Induction Agents Barbiturates eg thiopentone Propofol etomidate etc Opioids Benzodiazepines nitrous oxidehalothane isoflurane, desflurane, sevoflurane midozolam (fentanyl) Sufentanil remifentanil NMRELAXANTs 1.Suxa 2.Atracurium Cisat General Anesthetics Inhalational Parenteral * In the beginning there was ether & chloroform Slide 12 Phases of Anesthesia Induction: putting the patient to sleep Maintenance: keeping the patient asleep (without awareness) Emergence: waking the patient up (recovery) Slide 13 CNS Effects Increasing dose Coma Barbiturates Benzodiazepines Hypnosis Sedation, disinhibition, anxiolysis Possible selective anticonvulsant & muscle-relaxing activity Dose Response Relationships Anesthesia Medullary depression Slide 14 1. Intravenous agents primarily used for induction Barbiturates: thiopentone and methohexitone Benzodiazepines: midololam* lorezepam Etomidate Ketamine Propofol TIVA PROPOFOL (total IV anesthesia) CLASSIFICATION OF GENERAL ANESTHETICS B Slide 15 INTRAVENOUS ANAESTHETICS Rapid onset (seconds) Rapid awakening (minutes) Danger of overdose due to irrevocability of i.v. injection Redistribution determines duration of action Slide 16 2. Inhalational agents primarily used for maintenance 2a : Volatile agents Isoflurane Sevoflurane Desflurane Halothane, Enflurane Diethyl ether, chloroform, cyclopropane 2b: Anesthetic gases Nitrous Oxide- currently used Xenon- in the near future? GENERAL ANAESTHETICS CLASSIFICATION Slide 17 Mechanisms of Action 1.Enhanced GABA effect on GABA A Receptors Inhaled anesthetics - Etomidate Barbiturates- Propofol Benzodiazepines 2.Block nicotinic receptor subtypes (analgesia) Moderate to high concs of inhaled anesthetics 3.Activate K channels (hyperpolarize V m ) Nitrous oxide, ketamine, xenon 4.Inhibit NMDA (glutamate) receptors Nitrous oxide, ketamine, xenon, high dose barbiturates 5.Inhibit synaptic proteins ( NT release)(amnesia) 6.Enhance glycine effect on glycine Rs (immobility) Slide 18 Halogenated hydrocarbons (Volatile) Inhalational Agents Nitrous oxide (Gas) N O N Anesthesia machine work station Slide 19 Preanesthetic Medications Benzodiazepines Reduce anxiety Midazolam, diazepam Barbiturates Sedation Pentobarbital Antihistamines Prevention of allergic reactions Diphenhydramine Antiemetics Prevent aspiration of stomach contents Reduce postsurgical nausea and vomiting Ondansetrone Opioids Provide analgesia Fentanyl Anticholinergics Amnesia, prevent bradycardia, and fluid secretion Scopolamine Muscle relaxants Facilitation of intubation Slide 20 1.Rapid and pleasant induction 2.Rapid changes in the depth of anesthesia 3.Adequate muscle relaxation 4.Wide margin of safety 5.Absence of toxic/adverse effects 6. No emergence problems CHARACTERSITICS OF AN IDEAL ANAESTHETIC No single agent yet identified is an ideal anesthetic Slide 21 Anesthetic Uptake and Distribution Vessel Rich Group (VRG) CNS and visceral organs High blood flow (75%) and low capacity Muscle Group (MG) Skin and muscle Moderate flow and high capacity Fat Group (FG) Low flow and high capacity Vessel Poor Group Bone, cartilage, ligaments Low flow and low capacity Slide 22 Xe Isoflurane Halothane...... Cellular (synapses) Molecular (lipids & receptors) Search for the molecular mechanism(s) of general anesthesia Slide 23 Mechanism of action: Intravenous Anesthetics Cause anesthesia via GABAa receptors Specific selective targets Specific sites for specific effects Different anesthetics have different mechanisms Slide 24 Anesthetic of the Future: Xenon Rare gas extracted from air Very expensive to produce Close to ideal anesthetic Low blood and tissue solubility (rapid induction/recovery) Potent Not metabolized (totatally inert) Nonflammable Minimal side effects Slide 25 THERAPEUTIC GASES: Oxygen Administered to prevent hypoxic injury Hypoxia can result from: Hypoxemia (problem with lungs) Inadequate delivery to tissues Impaired utilization Can have toxic effects Due to free radical generation Slide 26 THERAPEUTIC GASES: Nitric Oxide Important cell signalling molecule Can selectively dilate pulmonary vasculature Administered to newborns with persistent pulmonary hypertension Under investigation for many disease states Can have toxic effects Slide 27 Immobilization in response to surgical incision (spinal cord) Sedation, loss of consciousness ( thalamic firing) Amnesia ( hippocampal neurotransmission) Regional Effects Slide 28 Parenteral Anesthetics (Intravenous) Most commonly used drugs to induce anesthesia Barbiturates (Thiopental* & Methohexital) Benzodiazepines (Midazolam) Opioids (Morphine & Fentanyl) Propofol* Etomidate * Most commonly used for induction Slide 29 Barbiturates & Benzodiazepines MOA: Barbiturates Benzodiazepines GABA 1) Both bind to GABA A receptors, at different sites Both cause increase Cl - influx in presence of GABA BNZ binding can be blocked by flumazenil 2) Barbs at high doses - are also GABA mimetic, block Na channels & NMDA/glutamate Rs Flumazenil - O (w/ & ) Slide 30 Classic Stages of Anesthesia* Stage 1: Analgesia decreased awareness of pain, amnesia Stage 2: Disinhibition delirium & excitation, enhanced reflexes, retching, incontinence, irregular respiration Stage 3: Surgical Anesthesia unconscious, no pain reflexes, regular respiration, BP is maintained Stage 4: Medullary Depression respiratory & CV depression requiring ventilation & pharmacologic support. * Seen mainly with Ether. Not all stages are observed with modern GAs. Slide 31 Barbiturates Thiopental & methohexital are highly lipid soluble & can produce unconsciousness & surgical anesthesia in Propofol (Diprivan ) Produces anesthesia as rapidly as i.v. barbs & but recovery is more rapid than w/ barbs. Recovery is not delayed after prolonged infusion (due to more rapid clearance).** Patients are able to ambulate sooner & patients feel better in the post-op period compared to other i.v. anesthetics. Antiemetic effects (pts w/ risk of nausea) Can cause marked hypotension (>barbs) Commonly used as component of balanced anesthesia for maintenance of anesthesia following induction of anesthesia. ** More rapid discharge from the recovery room Slide 34 Etomidate (Amidate ) Rapid induction (~1 min) Used as a supplement with nitrous oxide for short surgical procedures Short duration of action (3-5 mins) Hypnotic, but not analgesic Little effect on CV & Respiration Can cause post-op nausea & decrease cortisol production w/ long term infusion*. Primarily used in pts w/ limited cardiac or respiratory reserve (safer than barbs or propofol in pts w/ coronary artery dx., cardiomyopathy, etc.) * increased mortality Slide 35 Benzodiazepines Midazolam (> Diazepam & Lorazepam) Used to produce anxiolysis, amnesia & sedation prior to induction of GA w/ another agent. Sedative doses achieved w/in 2 min, w/ 30 min duration of action (short duration). Effects are reversed with flumazenil. Slide 36 Opioids (Morphine, Fentanyl & Remifentanil*) GAs do not produce effective analgesia (except for ketamine). Given before surgery to minimize hemodynamic changes produced by painful stimuli. This reduces GA requirements. High doses can cause chest wall rigidity & post-op respiratory depression Therapeutic doses will inhibit respiration ( CO 2 ) Used for post-op analgesia Remifentanil is an ester opioid metabolized by plasma esterases. It is very potent but w/ a short t 1/2 (3-10 mins). Slide 37 Ketamine A dissociative anesthetic that produces a cataleptic state that includes intense analgesia, amnesia, eyes open, involuntary limb movement, unresponsive to commands or pain. Increases heart rate & blood pressure (opposite of other GAs) Can be used in shock states (hypotensive) or patients at risk for bronchospasm. Used in children & young adults for short procedures Side Effects: nystagmus, pupillary dilation, salivation, Hallucinations & vivid dreams emergence delirium Slide 38 Inhaled Anesthetics Easily vaporized liquid halogenated hydrocarbons Administered as gases (gas) Slide 39 Inhaled Anesthetics Partial pressure or tension in inspired air is a measure of their concentration The speed of induction of anesthesia depends on: Inspired gas partial pressure (GA concentration) Ventilation rate GA solubility (less soluble GAs equilibrate more quickly with blood & into tissues such as the brain) Slide 40 Minimum Alveolar Concentration The minimum alveolar anesthetic concentration required to eliminate the response to a painful stimulus in 50% of patients A measure of GA potency. Its a population average. 1.3 MAC - 100% will not respond to stimuli. When several GAs are mixed, their MAC values are additive (e.g. nitrous oxide is commonly mixed w/ other anesthetics). MAC % Nitrous Oxide>100 Halothane0.75 Methoxyflurane0.16 Slide 41 MAC & Patient Conditions Pregnancy - MAC (elevated progesterone) Elderly - MAC (less brain activity) Chronic Alcoholics - MAC (cross-tolerance) Acute alcohol poisoning - MAC (additive) Bispectral Index Monitor (EEG) is used to measure a patients anesthetic depth. BIS LEVELCLINICAL STATE Awake Sedated Moderate hypnotic level (no recall) Deep hynotic level Isoelectric EEG 100 80 60 40 0 Slide 42 Elimination Anesthesia is most commonly terminated by redistribution of drug from brain to the blood & out through the lungs. The rate of recovery from anesthesia for GAs with low blood:gas PCs is faster than for highly soluble Gas. - Time is $$ in the O.R. & recovery room Blood:Gas PCoeff Haltothane 2.30 Desflurane 0.42 Sevoflurane 0.69 Halothane & methoxyflurane undergo hepatic metabolism & can cause liver & kidney toxicity.respectively Slide 43 Properties of Inhaled anesthetics Nitrous Oxide MAC > 100% : Incomplete anesthetic Good analgesia No metabolism Rapid onset & recovery Used along w/ other anesthetic; fast induction & recovery Halothane The first halogenated inhalational anesthetic Not pungent (use for induction w/ children)* Medium rate of onset & recovery Although inexpensive, its use has declined Sensitizes the heart to epi-induced arrhythmias Rare halothane induced hepatitis * fewer side effects also seen in children Slide 44 Properties of Inhaled anesthetics Desflurane Most rapid onset of action & recovery of the halogenated GAs (low PC) Widely used for outpatient surgery Irritating to the airway in awake patients & causes coughing, salivation & bronchospasm (poor induction agent) Used for maintenance of anesthesia Sevoflurane Very low blood:gas partition coefficient w/ relatively rapid onset of action & recovery * Widely used for outpatient surgery* Not irritating to the airway Useful induction agent, particularly in children * Similar to Desflurane Slide 45 Properties of Inhaled anesthetics Isoflurane Medium rate of onset & recovery Used for induction & maintenance of anesthesia Isoflurane was the most commonly used inhalational GA in the US. Has been largely replaced by Desflurane. Methoxyflurane Now widely considered obsolete Slow onset & recovery Extensive hepatic/renal metabolism, w/ release of F - ion causing renal dysfunction Slide 46 Toxicity Malignant Hyperthermia Esp. when halogenated GA used with succinylcholine Rx: dantrolene (immediately) Halothane: Halothane undergoes >40% hepatic metabolism Rare cases of postoperative hepatitis occur Halothane can sensitize the heart to Epi (arrhythmias) Methoxyflurane F release during metabolism (>70%) may cause renal insufficiency after prolonged exposure. Nitrous oxide Megoblastic anemia may occur after prolonged exposure due to decreases in methionine synthase activity(Vit B 12 deficiency). Slide 47 MUSCLE PHYSIOLOGY Neuromuscular Junction Skeletal muscles stimulated by motor neurons Components of somatic nervous system Nerves reside in brain or spinal cord Threadlike extensions travel to muscle cells Axon Divides profusely as it enters the muscle Each axonal ending forms branching neuromuscular junction with a single muscle fiber Only one neuromuscular junction per muscle fiber Slide 48 MUSCLE PHYSIOLOGY Neuromuscular Junction Axonal ending and muscle fiber very close Not touching 1 2 nanometers (nm) apart Separating space termed synaptic cleft Gel-like extracellular substance rich in glycoproteins Slide 49 NMJ Blockers(TWO TYPES) Depolarising & Nondepolarising Depolarising Agent Succinylcholine, Non Depolarising Agent Curare Type ie Atracurium Cisatracurium & Rocuronium relax skeletal muscle facilitate intubation** insure immobility Reversed by neostigmine* & glycopyrrolate* during post-op period * quaternary drugs; ** intubation is usually needed for airway maintenance & to prevent aspiration. Slide 50 DEPOLARIZER Slide 51 NON-DEPOLARIZERS Slide 52 Reversal NEOSTIGMINE AND ARTROOINE OR NEOSTIGMINE AND GLYCOPYROLATE Slide 53 Dantrolene Interfers with the release of calcium from the sarcoplasmic reticulum through the SR calcium channel complex. Used to prevent or reverse malignant hyperthermia (which is otherwise fatal in ~50% of cases w/o dantrolene). Given by i.v. push at the onset of symptoms (e.g. an unexpected rise in CO 2 levels) Supportive measures & 100% O 2 are also used to treat malignant hyperthermia Slide 54 Nausea & Vomiting General anesthetics effect the chemoreceptor trigger zone & brainstem vomiting center (cause nausea & vomiting) Rx: - Ondansetron (5-HT 3 antagonist) to prevent - Avoidance of N 2 O - Propofol for induction - Keterolac vs. opioid for analgesia - Droperidol, metaclopromide & dexamethasone Slide 55 The End